Inhibition of caspase-2 by a designed ankyrin repeat protein:: Specificity, structure, and inhibition mechanism

被引:102
作者
Schweizer, Andreas
Roschitzki-Voser, Heidi
Amstutz, Patrick
Briand, Christophe
Gulotti-Georgieva, Maya
Prenosil, Eva
Binz, H. Kaspar
Capitani, Guido
Baici, Antonio
Pluckthun, Andreas
Grutter, Markus G.
机构
[1] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland
[2] Univ Zurich Hosp, Dept Med, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland
[3] Mol Partners AG, CH-8952 Schlieren, Switzerland
关键词
D O I
10.1016/j.str.2007.03.014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network.
引用
收藏
页码:625 / 636
页数:12
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